Finding the perfect spot for fluorine: improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffold.

A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.

Structure-based drug design of RN486, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis.

Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.

Enantioselective organocatalysis using SOMO activation.

The asymmetric α-addition of relatively nonpolar hydrocarbon substrates, such as allyl and aryl groups, to aldehydes and ketones remains a largely unsolved problem in organic synthesis, despite the wide potential utility of direct routes to such products. We reasoned that well-established chiral amine catalysis, which activates aldehydes toward electrophile addition by enamine formation, could be expanded to this important reaction class by applying a single-electron oxidant to create a transient radical species from the enamine. We demonstrated the concept of singly occupied molecular orbital (SOMO) activation with a highly selective α-allylation of aldehydes, and we here present preliminary results for enantioselective heteroarylations and cyclization/halogenation cascades.

Rh(I)-catalyzed direct ortho-alkenylation of aromatic ketimines with alkynes and its application to the synthesis of isoquinoline derivatives.

[reaction: see text] Novel synthetic methods of both ortho-alkenylated aromatic ketones and isoquinoline derivatives have been developed through the Rh(I)-catalyzed direct ortho-alkenylation of common aromatic ketimines with alkynes. Furthermore, a highly efficient one-pot synthesis of isoquinoline derivatives was achieved by simply mixing aromatic ketone, benzylamine, and alkyne under a Rh(I) catalyst.

Isolation of the enhanced neurovirulent HSV-1 strains from Korean patients.

Herpes simplex virus type 1 (HSV-1) is a neurotropic DNA virus which has latency in human. In this study, we isolated various HSV-1 strains, named KHS, from the skin lesions of Korean patients and characterized the specific features of each strain. We found that KHS strains produced small, cell associated and nonsyncycial plaques in Vero cells. We classified KHS strains into two substrains, KHS 1 which had highly condensed plaques and KHS 2 which had less condensed plaques. Since gD protein of HSV-1 plays important roles in viral plaque formation, we determined the nucleotide sequences of gD genes of KHS strains. According to deduced amino acid sequences of gD protein in KHS strains compared with prototype strains KOS and F, we found that gD of KHS strains have more putative O-glycosidic sites, serine in KHS 1 and threonine in KHS 2, respectively. To find out the establishment of viral latency, we infected each virus strain into eyes of mice and carried out trigerminal ganglia explanting experiment. We found that both KHS strains established latent infections stably just as did the prototype KOS and F strains. The eye swab experiments were carried out to check the viral replication in vivo. KHS 1 exhibited a longer shedding time in eyes of mice. We also found that KHS 1 has a higher neurotropic affinity by determining the time it took for the virus to reach the trigerminal ganglia from the eyes. Currently, we are studying the possible mechanism of high neuroinvasiveness of KHS 1 strain.

Chelation-assisted Rh(I)-catalyzed ortho-alkylation of aromatic ketimines or ketones with olefins.

Described herein is the Rh(I)-catalyzed ortho-alkylation of aromatic ketimines or ketones with olefins. This method showed high reactivity and selectivity to monoalkylation for a variety of olefins including 1-alkenes with an allylic proton, alpha,omega-dienes, and internal olefins. For a mechanistic study, H/D exchange experiments were carried out, which demonstrated that the ortho C-H bond could be easily cleaved even at the low temperature of 45 degrees C. The key step of this reaction is the formation of a stable five-membered metallacycle by a chelation-assisted ortho C-H bond activation. Furthermore, the direct ortho-alkylation of aromatic ketones with the Rh(I) complex was successfully achieved by adding 50 mol % of benzylamine as a chelation-assistant tool.